Dosificación de vancomicina en pacientes sometidos a diálisis intermitente. Elaboración de un protocolo de dosificación inicial / Vancomycin dosage in patients undergoing intermittent dialysis. Preparation of an initial dosage protocol

Objetivo: Revisar la dosis inicial de vancomicina en pacientes en hemodiálisis intermitente, para establecer un protocolo de dosificación que permita alcanzar una concentración pre-diálisis óptima (15-20 µg/ml) tras la dosis de carga y primera dosis de mantenimiento.Método: Estudio observacional, retrospectivo, unicéntrico en el que se incluyeron todos los pacientes en hemodiálisis (HD) que recibieron vancomicina durante la última hora de la sesión entre septiembre de 2010 y enero de 2018.Resultados: Se incluyeron 87 pacientes, considerando el valor óptimo de Cmin=15-20 µg/ml, solo el 12,6% de los pacientes tras la dosis de carga y el 18,4% tras la dosis de mantenimiento alcanzaron el valor de referencia.Conclusiones: La pauta empírica inicial de vancomicina fue insuficiente en la mayoría de los pacientes para alcanzar concentraciones óptimas desde el inicio del tratamiento, por lo que se propone un nuevo protocolo de dosificación adaptado al peso del paciente. (AU)

Objective: To review the initial dosage of vancomycin in patients on intermittent hemodialysis, to establish a dosing protocol that allows reaching an optimal pre-dialysis concentration (15-20 µg/ml) after loading dose and first maintenance dose.Method: Observational, retrospective, unicentric study in which all hemodialysis (HD) patients who received vancomycin, during the last hour of the session, between September 2010 and January 2018, were included.Results: 87 patients were included, considering the value optimal Cmin=15-20 µg/ml, only 12.6% of the patients after the loading dose and 18.4% after the maintenance dose reached the reference value.Conclusions: The initial empirical regimen of vancomycin was insufficient in most patients to reach optimal concentrations from the beginning of treatment, so a new dosing protocol adapted to the patient’s weight is proposed. (AU)

[Pharmacogenetic analysis of the absorption kinetics of cyclosporine in a population of Spanish cardiac transplant patients]. / Análisis farmacogenético de la cinética de absorción de ciclosporina en una población española de pacientes trasplantados cardíacos.

OBJECTIVE: To determine how single nucleotide polymorphisms located on genes MDR1, CYP3A4 and CYP3A5 affect the absorption kinetics of cyclosporine in cardiac transplant patients. METHOD: We selected a sample of 30 adult patients having previously undergone a primary cardiac transplant and who had received cyclosporine as an immunosuppressant. During the first month after the transplant, we performed a pharmacokinetic study of each patient to determine values in the cyclosporine concentration area under the 12-hour curve, steady-state cyclosporine concentration, maximum cyclosporine concentration, and time to reach that concentration. Single nucleotide polymorphisms were genotyped in all patients: MDR1 3435C > T, CYP3A4-390A > G and CYP3A5 6986A > G. RESULTS: Being a carrier of the T-allele for polymorphism MDR1 3435C > T is associated with higher values in the cyclosporine concentration area under the 12-hour curve (p = 0.01) and in steady-state cyclosporine concentration (p = 0.05), compared with those from patients who do not carry that allele. DISCUSSION: Our results show that genotype differences in MDR1 3435C > T can explain part of the variability in cyclosporine absorption among individuals in the population of Spanish cardiac transplant recipients.

Análisis farmacogenético de la cinética de absorción de ciclosporina en una población española de pacientes trasplantados cardíacos / Pharmacogenetic analysis of the absorption kinetics of cyclosporine in a population of Spanish cardiac transplant patients

Objetivo: Determinar el papel de polimorfismos de nucleótido único localizados en los genes MDR1, CYP3A4 y CYP3A5 sobre la cinética de absorción de ciclosporina en pacientes trasplantados cardíacos. Método: Se seleccionó una muestra de 30 pacientes adultos sometidos a un primer trasplante de corazón que habían recibido ciclosporina como tratamiento inmunosupresor. En el primer mes después del trasplante se realizó un estudio farmacocinético a cada paciente para determinar los valores del área de concentración de ciclosporina bajo la curva de 12 h, concentración de ciclosporina en estado de equilibrio, concentración de ciclosporina máxima y el tiempo en alcanzar dicha concentración. En todos los pacientes se genotipificaron los polimorfismos de nucleótido único: MDR1 3435C > T, CYP3A4-390A > G y CYP3A5 6986A > G. Resultados: Ser portador del alelo T para el polimorfismo MDR1 3435C > T se asoció a valores mayores de área de concentración de ciclosporina bajo la curva de 12 h (p = 0,01) y de concentración de ciclosporina en estado de equilibrio (p = 0,05), en comparación con los pacientes no portadores de dicho alelo. Discusión: Nuestros resultados muestran que las diferencias genotípicas de MDR1 3435C > T podrían explicar parte de la variabilidad interindividual en la absorción de la ciclosporina en la población española de trasplantados cardíacos (AU)

Objective: To determine how single nucleotide polymorphisms located on genes MDR1, CYP3A4 and CYP3A5 affect the absorption kinetics of cyclosporine in cardiac transplant patients. Method: We selected a sample of 30 adult patients having previously undergone a primary cardiac transplant and who had received cyclosporine as an immunosuppressant. During the first month after the transplant, we performed a pharmacokinetic study of each patient to determine values in the cyclosporine concentration area under the 12-hour curve, steady-state cyclosporine concentration, maximum cyclosporine concentration, and time to reach that concentration. Single nucleotide polymorphisms were genotyped in all patients: MDR1 3435C > T, CYP3A4-390A > G and CYP3A5 6986A > G. Results: Being a carrier of the T-allele for polymorphism MDR1 3435C > T is associated with higher values in the cyclosporine concentration area under the 12-hour curve (p = 0.01) and in steady-state cyclosporine concentration (p = 0.05), compared with those from patients who do not carry that allele. Discussion: Our results show that genotype differences in MDR1 3435C > T can explain part of the variability in cyclosporine absorption among individuals in the population of Spanish cardiac transplant recipients (AU)

[Stability and in vitro activity of voriconazole eyedrops at a concentration of 3 microg/mL]. / La estabilidad y actividad in vitro de voriconazol en colirio a una concentración de 3 microg/mL.

OBJECTIVE: To assess the stability and activity of voriconazole 3 microg/mL eyedrops as prepared for use against amphotericin B- and fluconazole-resistant fungal endophthalmitis. METHOD: Stability (concentration using UV-spectrophotometry; pH, osmolarity, and particle formation) and sterility were analyzed under various preservation conditions--room temperature (22-24 degrees C) or refrigerated (2-8 degrees C). The preparation's in vitro efficacy was analyzed using the standard National Committee for Clinical Laboratory Standards method for 30 days. RESULTS: Voriconazole concentrations were found to be within limits allowed by the United Stated Pharmacopeia (90-115%). pH (room temperature: 6.96-7.60; refrigerated: 6.84-7.21) and osmolarity (room temperature: 265-284 mOsm/l; refrigerated: 270-285 mOsm/l) remained within eye physiological ranges throughout the study under the analyzed conditions. The preparation s antifungal activity remained stable during the first three weeks. CONCLUSIONS: The voriconazole 3 microg/mL eyewash preparation remained stable, sterile and with full antifungal activity for 21 days when stored both at room temperature and under refrigeration conditions.

Estabilidad y actividad in vitro de voriconazol en colirio a una concentración de 3 µg/mL / Stability and in vitro activity of voriconazole eyedrops at a concentrations of 3 mg/mL

Objetivo: Evaluar la estabilidad y actividad de un colirio devoriconazol 3 µg/mL, preparado para su uso en endoftalmitis fúngicasresistentes a anfotericina B y fluconazol.Método: Se analizaron la estabilidad (concentración medianteespectrofotometría-UV; pH, osmolaridad y aparición de partículas)y la esterilidad bajo condiciones de conservación diferentes:temperatura ambiente (22-24 °C) o refrigerado (2-8 °C) y la eficaciain vitro del preparado, mediante el método estándar delNacional Committee for Clinical Laboratory Standards duranteun periodo de 30 días.Resultados: Las concentraciones de voriconazol se encontrarondentro de los márgenes permitidos por la United StatesPharmacopeia (90-115%). El pH (ambiente 6,96-7,60; refrigerado:6,84-7,21) y la osmolaridad (ambiente: 265-284 mOsm/l;refrigerado: 270-285 mOsm/l) se mantuvieron en los intervalosfisiológicos para el ojo, a lo largo de todo el estudio en las doscondiciones analizadas. La actividad antifúngica del colirio permanecióestable durante las tres primeras semanas.Conclusiones: El colirio preparado de voriconazol 3 µg/mLpermanece estable, estéril y con plena actividad antifúngica durante21 días cuando se almacena tanto a temperatura ambientecomo en refrigeración

Objective: To assess the stability and activity of voriconazole3 µg/mL eyedrops as prepared for use against amphotericin Bandfluconazole-resistant fungal endophthalmitis.Method: Stability (concentration using UV-spectrophotometry;pH, osmolarity, and particle formation) and sterility were analyzedunder various preservation conditions – room temperature(22-24 °C) or refrigerated (2-8 °C ). The preparation's in vitroefficacy was analyzed using the standard National Committee forClinical Laboratory Standards method for 30 days.Results: Voriconazole concentrations were found to be withinlimits allowed by the United Stated Pharmacopeia (90-115%). pH(room temperature: 6.96-7.60; refrigerated: 6.84-7.21) andosmolarity (room temperature: 265-284 mOsm/l; refrigerated:270-285 mOsm/l) remained within eye physiological rangesthroughout the study under the analyzed conditions. The preparation'santifungal activity remained stable during the first threeweeks.Conclusions: The voriconazole 3 µg/mL eyewash preparationremained stable, sterile and with full antifungal activity for 21days when stored both at room temperature and under refrigerationconditions

[Tacrolimus blood levels and incidence of graft rejection in heart transplantation]. / Relación entre los niveles de tacrolimus en sangre y la incidencia de rechazo en enfermos trasplantados de corazón.

OBJECTIVE: To determine the relationship between pharmacokinetic parameters and clinical outcomes after heart transplantation and to determine the range of tacrolimus blood levels which provides the most effective protection against graft rejection. To study other factors that predict graft rejection. METHOD: We retrospectively analyzed the clinical outcomes of all adult patients who received a heart transplant between January 2000 and October 2003 and had routine monitoring of tacrolimus trough levels at the time of scheduled endomyocardial biopsy. Rejection was defined as Grade = 3, based on the International Society for Heart and Lung Transplantation (ISHLT) criteria. The follow-up period was 1 year. All patients were on a triple therapy regimen of Tacrolimus (TAC), Corticosteroids and Azatioprine/Micophenolate Mofetil. Data were analyzed by Student s t-test, univariate logistic regression and ROC curve. RESULTS: Tacrolimus blood levels measured at day +5 postransplant were the strongest predictor of acute graft rejection over a 1-year follow-up period (rejection 5.76 +/- 3.4 ng/ml vs no rejection 9.66 +/- 2.73 ng/ml, p = 0.016). A decrease of one unit in TAC trough level values at day +5 postransplant implied a 1.58 greater risk of rejection (p = 0.05). Overall incidence of treated acute rejection was lower for patients with trough levels higher than 8 ng/ml on day +5 postransplant (33 vs 80%, p = 0.055, Fisher s exact test). CONCLUSIONS: Data suggest that in heart transplant patients it may be crucial to achieve tacrolimus levels of at least 8 ng/ml during the first days postsurgery to avoid rejection.

Relación entre los niveles de tacrolimus en sangre y la incidencia de rechazo en enfermos trasplantados de corazón / Tacrolimus blood levels and incidence of graft rejection in heart transplantation

Objetivo: Evaluar la relación entre los niveles en sangre de tacrolimus, la incidencia de rechazo agudo en enfermos trasplantados de corazón y determinar el rango de concentración más adecuado para prevenir el rechazo. Estudiar otros factores predictores del rechazo. Método: Se realizó un estudio retrospectivo de todos los enfermos adultos trasplantados de corazón entre enero de 2000 y octubre de 2003 en tratamiento con tacrolimus, corticoides y azatioprina/ micofenolato mofetil. La eficacia del tratamiento se evaluó por confirmación histopatológica del rechazo agudo como grado ≥ 3A según criterios del Sociedad Internacional de Trasplante de Pulmón y Corazón (ISHLT). Se registraron los resultados de las biopsias endomiocárdicas y de los niveles mínimos de tacrolimus en sangre durante el primer año postrasplante. El análisis de los datos se realizó mediante la t de Student, regresión logística univariante y curva ROC. Resultados: Se encontraron diferencias significativas en la concentración mínima de tacrolimus en sangre alcanzada el día +5 postrasplante entre los enfermos que presentaron algún episodio de rechazo agudo el primer año y los que no (5,76 ± 3,4 vs 9,66 ± 2,73 ng/ml, p = 0,016). El nivel el día +5 fue el mejor predictor del rechazo (p = 0,05) de modo que el riesgo de un paciente respecto a otro con una unidad menos en el nivel de tacrolimus es 1,58 veces mayor. 8 ng/ml es el nivel con mayor poder de discriminación (sensibilidad = 75% y especificidad = 72,7%), de modo que alcanzar una concentración mínima en sangre de 8 ng/ml el día +5 reduce la incidencia de rechazo agudo de 33 a 80% (p = 0,055, p. exacta de Fisher). Conclusiones: Alcanzar niveles mínimos adecuados de tacrolimus en los primeros días postrasplante (al menos de 8 ng/ml el día +5) puede ser crucial para evitar el rechazo agudo en pacientes trasplantados de corazón

Objective: To determine the relationship between pharmacokinetic parameters and clinical outcomes after heart transplantation and to determine the range of tacrolimus blood levels which provides the most effective protection against graft rejection. To study other factors that predict graft rejection. Method: We retrospectively analyzed the clinical outcomes of all adult patients who received a heart transplant between January 2000 and October 2003 and had routine monitoring of tacrolimus trough levels at the time of scheduled endomyocardial biopsy. Rejection was defined as Grade ≥ 3, based on the International Society for Heart and Lung Transplantation (ISHLT) criteria. The follow-up period was 1 year. All patients were on a triple therapy regimen of Tacrolimus (TAC), Corticosteroids and Azatioprine/Micophenolate Mofetil. Data were analyzed by Student’s t-test, univariate logistic regression and ROC curve. Results: Tacrolimus blood levels measured at day +5 postransplant were the strongest predictor of acute graft rejection over a 1- year follow-up period (rejection 5.76 ± 3.4 ng/ml vs no rejection 9.66 ± 2.73 ng/ml, p = 0.016). A decrease of one unit in TAC trough level values at day +5 postransplant implied a 1.58 greater risk of rejection (p = 0.05). Overall incidence of treated acute rejection was lower for patients with trough levels higher than 8 ng/ml on day +5 postransplant (33 vs 80%, p = 0.055, Fisher’s exact test). Conclusions: Data suggest that in heart transplant patients it may be crucial to achieve tacrolimus levels of at least 8 ng/ml during the first days postsurgery to avoid rejection

New strategies of cyclosporine monitoring in heart transplantation: initial results.

The aim of this study was to evaluate cyclosporine (CyA) absorption profiles in heart transplantation to establish the most adequate monitoring strategy and determine the optimal therapeutic range for AUC(0-4) or C2 levels. A total of 22 full pharmacokinetic studies were performed at steady-state in 22 adult heart transplant recipients (18 men, 4 women). Twelve studies were performed during the first month posttransplant (group I), and 10 studies were done after 1 month (group II). In 9 outpatients we performed an abbreviated AUC(0-4). The mean age of the patients was 49+/-15 years (range, 15-72 years), and the mean weight was 70.4+/-10.8 kg (mean, 54-98 kg). The CyA dosage had been adjusted to maintain trough levels (C0) in the putative target ranges of 200 to 400 ng/mL in group I and between 100 to 300 ng/mL in group II. Blood samples were drawn prior to and at 0.5, 1, 2, 4, 6, 8, and 12 hours after the morning dose. The CyA blood levels were measured by the AxSYM cyclosporine assay. The AUC was calculated by the trapezoidal rule. Multiple linear regression was done to evaluate the predictive ability of various limited sampling strategies. The C0 correlated poorly, either with the full AUC (r2=0.64) or the AUC(0-4) (r2=0.43), while C2 seemed to be the most accurate single predictor of drug exposure (r2=0.92 for AUC(0-12); r2=0.74 for AUC(0-4)). For both AUC(0-4) and AUC(0-12), all 2- or 3-point strategies had r2 values approaching that of the C2 value. In conclusion, C2 is a simple, fast, and accurate value to predict AUC(0-4) in routine clinical practice. Its implementation must focus on ensuring the commitment of all unit staff, thus ensuring that patients are sampled on time and minimizing the impact on workload.

Clinical pharmacokinetics of tacrolimus in heart transplantation: new strategies of monitoring.

The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart transplant patients in order to find the best sampling time to predict the total exposure and to explore the target range for optimal clinical immunosuppression. Twenty-five full pharmacokinetic studies were performed in 22 heart transplant patients (11 men and 7 women) at less than 1 year posttransplant. The immunosuppressive treatment was steroids plus azathioprine or mycophenolate mofetil and TAC. The mean age was 55 years (36-64 years) and the mean weight 70.49 kg (50-111 kg). After three days of receiving the same dose, eight blood samples were collected at 0.5, 1, 2, 4, 6, 8, and 12 hours postmorning dose. TAC concentrations were measured by microparticle enzyme immunoassay (IMx). Area under the concentration-time curve(AUC(0-12)) was calculated by the trapezoidal rule. Using 0-4 hours TAC blood concentrations, a projected 12 hours AUC (extrapolated AUC(0-4)) was calculated assuming C0 and C12 were comparable. A high interpatient TAC pharmacokinetics variability that was greater during the absorption phase was observed. A Cmax (30.5+/-13.8 ng/mL) was reached at 2.3+/-1.5 h. When target trough levels were achieved (10-20 ng/mL), the mean tacrolimus exposure was 230.6+/-59.2 ng h/mL (120.14-327.7) (n=19). Correlation between AUC(0-12) and C0 was relatively good (r2=0.74). Between individual time points, C4 showed the best correlation (r2=0.88). In any case the best strategy to monitor is to obtain the extrapolated AUC(0-4) (r2=0.98), as a good approach to patients with a poor response to treatment.

[Aluminum contamination of pediatric parenteral nutrition solutions]. / Contaminación por aluminio de las soluciones de nutrición parenteral pediátrica.

The main clinical manifestations of aluminum toxicity include progressive encephalopathy, osteomalacia, microcytic hypochromic anemia, and cholestasis. The premature newborn receiving IV therapy are at high risk of such aluminium intoxication: two conditions predispose them to an aluminum overdose-parenteral exposure and their reduced kidney function. The amount of aluminum present as contaminant was calculated for each of the i.v. solutions used in the preparation of the parenteral nutrition units in pediatrics, along with that for three prepared nutritions. This was done using atomic absorption spectrophotometry. The calcium salts (5.18 +/- 2.88(5)ppm), phosphorus salts (3.96 +/- 3.52(5)ppm) and trace elements (1.52 +/- 0.92(4) ppm) were the most contaminated components, the amount of aluminum being similar to that found by other authors showing bone and liver accumulations. The great variability between the solutions of different manufacturers and of different batches suggests that the contamination takes place during manufacture, so that it could in many cases be prevented by establishing adequate controls.